Norepinephrine Release and Clearance

What is the source of elevated NE levels in OSA? Venous and arterial NE levels reflect not only release, but metabolic degradation reuptake, diffusion, and regional and local circulation. Catecholamines are cleared by reuptake into nerves (referred to as uptake 1) and by uptake into nonneuronal tissue (referred to as uptake 2). NE is cleared by uptake 1 more than other catecholamines.

Tracer amounts of radiolabeled NE can be used to measure the release rate and the clearance rate of NE, which provide insight into the factors that contribute to circulating levels. We measured NE kinetics to determine whether the elevated NE levels in OSA result from an enhanced NE release rate and/or decreased NE clearance rate.

The basis of the NE kinetics technique is that if the rate at which NE is cleared from the plasma is known and the plasma level of NE is known, then the rate at which NE appears in the plasma can be calculated. This is known as the NE spillover or release rate. A relatively simple method for evaluating NE clearance rate and halflife is to infuse radiolabeled NE ([3H]-NE) until constant blood levels are attained and then measure the disappearance rate of the [3H]-NE in sequential blood samples (Ziegler, Kennedy, Morrissey, and O'Connor 1990). The release and clearance of NE can be calculated by the following formulae:

3 H-NE per liter plasma

NE release rate(ng/min) = clearance x plasma NE(ng/l)

We measured NE clearance and release rates in supine OSA subjects using 3H-NE of >98% radiochemical purity (New England Nuclear, Boston, MA). 3H-NE was infused into an antecubital vein at 1.5 ^Ci/min for 10 min. The infusion rate was then decreased to 0.78 ^Ci/min. Plateau levels are obtained in less than 1 h with this technique. Blood samples were drawn from the antecubital vein of the contralateral arm to measure plasma NE and 3H-NE levels during the infusion and for 16 min after the infusion was terminated. Plasma NE levels were measured by the radioenzymatic method of Kennedy and Ziegler (1990).

Since patients with OSA are often hypertensive, we measured NE clearance and release rate in a group of 65 apneics and hypertensives. Subjects were studied while breathing room air and a hypoxic gas mixture (Ziegler et al. 1997).

Consistent with prior studies, OSA patients had higher plasma NE across all conditions compared to non-OSA subjects (p < 0.01). We found that NE clearance increased significantly from 3.2 to 3.9 l/min when subjects breathed the hypoxic gas mixture (p < 0.001). Hypoxia also increased the NE-release rate from 892 to 1042 ng/min (p < 0.001) and increased the NE-release rate more among OSA patients than nonapneics (p < 0.001).

Normotensive apneics had the largest increase in NE release during hypoxia (p < 0.01). Apneics tended to have lower rates of NE clearance than nonapneics (p < 0.08) (Fig. 15.3).

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2.40

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Figure 15.3. NE clearance in OSA and nonapnea. Patients with OSA tended toward lower rates of NE clearance than nonapneic controls (Ziegler et al. 1997).

The results of these NE kinetics studies suggested that individuals with OSA are subject to transient increases in sympathetic activity, that hypertensive apneics maintain increased sympathetic nervous release of NE in the daytime, and that individuals with OSA tend to have reduced NE clearance.

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Figure 15.3. NE clearance in OSA and nonapnea. Patients with OSA tended toward lower rates of NE clearance than nonapneic controls (Ziegler et al. 1997).

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